Carcinogenesis Studies of Eugenol (CAS No. 97-53-0) in F344/N Rats and B6C3F1 Mice (Feed Studies).
Carcinogenesis studies of eugenol (>99% pure), a widely used flavor additive and chemical intermediate, were conducted by feeding diets containing 6,000 or 12,500 ppm of eugenol to groups of 50 female F344/N rats and by feeding diets containing 3,000 or 6,000 ppm to groups of 50 male F344/N rats and B6C3F1 mice of each sex for 103 weeks. Groups of 40 rats and 50 mice of each sex served as controls. Dose levels selected for the two year studies were based on thirteen-week (91-day) studies in which dietary concentrations for the six groups ranged from 0 to 12,500 ppm. Other than a -10% difference from controls in body weights in the 12,500 ppm male rats, no chemically related gross or histopathologic effects were observed. In the two-year studies, with the exception of the high dose female rats and female mice, final body weights of the treated groups were comparable to their respective controls. No significant differences in survival were apparent for any of the eight groups receiving eugenol and for the appropriate controls. Food consumption among groups was not different in comparison with controls-- rats: males equal to or greater than 97%, females equal to or greater than 91%; mice: males equal to or greater than 94%, females equal to or greater than 90%. There were no significant observable differences between treated and control groups of rats for either nonneoplastic (toxic) lesions or neoplasms that could be attributed to eugenol. Increases in tumor incidences were diagnosed for low dose male rats with alveolar, bronchiolar adenomas or carcinomas (combined), for C-cell adenomas of the thyroid gland in low dose female rats, and for endometrial stromal polyps of the uterus in high dose female rats. Fibroadenomas of the mammary gland were decreased in dosed groups of female rats compared with controls. None of these differences were considered to be associated with the dietary administration of eugenol. In male mice, the low dose animals had an increased incidence (P<0.05) of both hepatocellular adenomas (control, 4/50; low dose, 13/50; high dose, 10/49) and hepatocellular carcinomas (10/50, 20/50, 9/49) when compared with control animals. A significant increase in hepatic neoplasms was not observed in high dose animals. No single liver tumor type was observed in female mice with a statistically significant increased incidence. When the incidences of female mice with hepatocellular adenoma or carcinoma were combined (2/50, 7/49, 9/49), there was a dose-related positive trend and the incidence of liver neoplasms in high dose animals was higher than in controls (P<0.05). Eugenol was given in the diets of female F344/N rats (0, 0.6, or 1.25%) and of male F344/N rats and male and female B6C3F1 mice (0, 0.3, or 0.6%) for 103 weeks. Under these experimental conditions, there was no evidence of carcinogenicity observed for male or female rats. For mice there was equivocal evidence of carcinogenicity since eugenol caused increased incidences of both carcinomas and adenomas of the liver in male mice at the 3,000 ppm dietary level and because eugenol was associated with an increase in the combined incidences of hepatocellular carcinomas or adenomas in female mice. Levels of Evidence of Carcinogenicity: Male Rats: Negative Female Rats: Negative Male Mice: Equivocal Female Mice: Equivocal Synonym: 1-allyl-3-methoxy-4-hydroxybenzene


Pediatric feeding disorder and growth decline following mandibular distraction osteogenesis.
Mandibular distraction osteogenesis has proven to be an effective treatment for upper airway obstruction related to micrognathia. Changes in the aerodigestive space can help facilitate tracheostomy removal in children and prevent tracheostomy in newborns. However, this may also precipitate changes in the ability to orally feed. There are few data on early postoperative feeding and growth rate following mandibular lengthening. The authors found evidence of growth rate decline and feeding difficulty in pediatric patients following mandibular distraction osteogenesis. Ten pediatric patients underwent mandibular distraction osteogenesis for treatment of upper airway obstruction. Outcomes in resolution of upper airway obstruction, oral feeding success, and growth rate were analyzed. Follow-up ranged from 12 to 28 months. All 10 patients had complete resolution of upper airway obstruction. The length of distraction ranged from 10 to 17 mm. Three patients demonstrated a feeding disorder after mandibular distraction osteogenesis, defined as requiring a long-term (>1 month) alternate feeding method (gastric tube in two patients and gastric gavage in one). Seven of 10 patients exhibited an early decline in growth rate following distraction. Data used to determine growth rate changes were weight measurements at the time of distraction, at the time of distractor removal (6 to 8 weeks after distraction), and at 6 and 12 months after the date of distraction initiation. These results suggest that infants and children undergoing mandibular lengthening by distraction osteogenesis should be carefully monitored for postdistraction feeding disorder and growth rate disturbance.


RIM1 and RIM2 redundantly determine Ca2+ channel density and readily releasable pool size at a large hindbrain synapse.
The localization and density of voltage-gated Ca(2+) channels at active zones are essential for the amount and kinetics of transmitter release at synapses. RIM proteins are scaffolding proteins at the active zone that bind to several other presynaptic proteins, including voltage-gated Ca(2+) channel α-subunits. The long isoforms of RIM proteins, which contain NH2-terminal Rab3- and Munc13-interacting domains, as well as a central PDZ domain and two COOH-terminal C2 domains, are encoded by two genes, Rim1 and Rim2. Here, we used the ideal accessibility of the large calyx of Held synapse for direct presynaptic electrophysiology to investigate whether the two Rim genes have redundant, or separate, functions in determining the presynaptic Ca(2+) channel density, and the size of a readily releasable vesicle pool (RRP). Quantitative PCR showed that cochlear nucleus neurons, which include calyx of Held generating neurons, express both RIM1 and RIM2. Conditional genetic inactivation of RIM2 at the calyx of Held led to a subtle reduction in presynaptic Ca(2+) current density, whereas deletion of RIM1 was ineffective. The release efficiency of brief presynaptic Ca(2+) "tail" currents and the RRP were unaffected in conditional single RIM1 and RIM2 knockout (KO) mice, whereas both parameters were strongly reduced in RIM1/2 double KO mice. Thus, despite a somewhat more decisive role for RIM2 in determining presynaptic Ca(2+) channel density, RIM1 and RIM2 can overall replace each other's presynaptic functions at a large relay synapse in the hindbrain, the calyx of Held.


Permanent molars: delayed development and eruption.
Delayed development and eruption of all the permanent molars is a rare phenomenon, which can cause disturbance in the developing occlusion. The eruption of permanent first and second molars is very important for the coordination of facial growth and for providing sufficient occlusal support for undisturbed mastication. In the case described, the first permanent molars were delayed in their development and were seen erupting at the age of nine and a half years. Severe disparity between the left and the right side of the dentition with respect to the rate of development of molars were also present.


Effects of fasting on solid organ transplant recipients during Ramadan - a practical guide for healthcare professionals.
Fasting in the month of Ramadan is an obligatory act for healthy adult Muslims. It requires abstinence from food and drink from dawn to sunset. Although there are exemptions from fasting, many patients are keen to fulfil what they see as a religious obligation, even if this may be against medical advice in some cases. Solid organ transplant (SOT) recipients often ask healthcare professionals for advice on fasting. Studies on the effect of fasting in transplant patients have all been done in the Middle East and North Africa where the average fasting duration is between 12 and 14 hours. In comparison, in temperate regions in the summer, fasting duration can be as long as 20 hours. Fasting when patients have to take immunosuppression 12 hours apart with little time variation poses unique challenges. In this review, current literature is reviewed, and a decision-making tool has been developed to assist clinicians in discussing the risks of fasting in transplant recipients, with consideration also given to circumstances such as the COVID-19 pandemic.Our review highlights that SOT recipients wishing to fast should undergo a thorough risk assessment, ideally 3 months before Ramadan. They may require medication changes and a plan for regular monitoring of graft function and electrolytes in order to fast safely. Recommendations have been based on risk tiers (very high risk, high risk and low/moderate risk) established by the International Diabetes Federation and the Diabetes and Ramadan International Alliance. Patients in the 'very high risk' and 'high risk' categories should be encouraged to explore alternative options to fasting such as winter fasting or Fidyah. Those in the 'low/moderate' category may be able to cautiously fast with guidance from their clinician. Prior to the commencement of Ramadan, all patients must receive up-to-date education on sick-day rules, instructions on when to terminate their fast or abstain from fasting.


Evolving concepts of assessment in a competency-based world.
Competency-based medical education (CBME) is an approach to the design of educational systems or curricula that focuses on graduate abilities or competencies. It has been adopted in many jurisdictions, and in recent years an explosion of publications has examined its implementation and provided a critique of the approach. Assessment in a CBME context is often based on observations or judgments about an individual's level of expertise; it emphasizes frequent, direct observation of performance along with constructive and timely feedback to ensure that learners, including clinicians, have the expertise they need to perform entrusted tasks. This paper explores recent developments since the publication in 2010 of Holmboe and colleagues' description of CBME assessment. Seven themes regarding assessment that arose at the second invitational summit on CBME, held in 2013, are described: competency frameworks, the reconceptualization of validity, qualitative methods, milestones, feedback, assessment processes, and assessment across the medical education continuum. Medical educators interested in CBME, or assessment more generally, should consider the implications for their practice of the review of these emerging concepts.


Acute changes in high-density lipoprotein cholesterol with exercise of different intensities.
The purpose of this study was to investigate the acute effects of exercise on plasma high-density lipoprotein cholesterol (HDL-C) and to determine whether the magnitude of this response would be affected by the intensity of the exercise. Twelve men (19-41 yr) ran an equivalent distance (9-12 km) on a treadmill on two separate occasions. On one occasion the exercise was performed at a speed that elicited 60% of the subject's maximal O2 uptake (VO2max), and on the other occasion exercise was performed at a speed that elicited 90% of VO2max. Changes in total cholesterol, triglycerides (TG), HDL-C, HDL apoprotein A (HDL-A), HDL saturation, lactate (LA), and free fatty acids (FFA) were measured during the course of each run, and all values were corrected for changes in plasma volume as indicated by hematocrit. There were significant increases (P less than 0.01) in HDL-C, HDL-A, and HDL saturation with exercise at both intensities, but greater increases in HDL-C (25 vs. 14%) and HDL-A (18 vs. 8%) were observed with the higher intensity exercise. Plasma FFA and TG did not differ between conditions, but LA concentrations rose significantly during the high-intensity exercise. These results indicate that increases in HDL components can occur with a relatively moderate exercise session and that the magnitude of these increases are directly related to the exercise intensity.


JNK pathway-associated phosphatase dephosphorylates focal adhesion kinase and suppresses cell migration.
JNK pathway-associated phosphatase (JKAP, also named DUSP22) is expressed in various tissues, indicating that JKAP may have an important biological function. We showed that JKAP localized in the actin filament-enriched region. Expression of JKAP reduced cell migration, whereas a JKAP mutant lacking catalytic activity promoted cell motility. JKAP efficiently removed tyrosine phosphorylation of several proteins. We have identified focal adhesion kinase (FAK) as a substrate of JKAP. Overexpression of JKAP, but not JKAP mutant lacking catalytic activity, decreased FAK phosphorylation at tyrosines 397, 576, and 577 in H1299 cells. Consistent with these results, decreasing JKAP expression by RNA interference promoted cell migration and Src-induced FAK phosphorylation. Taken together, this study identified a new role for JKAP in the modulation of FAK phosphorylation and cell motility.


Effects of synaptic synchrony on the neuronal input-output relationship.
The firing rate of individual neurons depends on the firing frequency of their distributed synaptic inputs, with linear and nonlinear relations subserving different computational functions. This letter explores the relationship between the degree of synchrony among excitatory synapses and the linearity of the response using detailed compartmental models of cortical pyramidal cells. Synchronous input resulted in a linear input-output relationship, while asynchronous stimulation yielded sub- and supraproportional outputs at low and high frequencies, respectively. The dependence of input-output linearity on synchrony was sigmoidal and considerably robust with respect to dendritic location, stimulus irregularity, and alteration of active and synaptic properties. Moreover, synchrony affected firing rate differently at lower and higher input frequencies. A reduced integrate-and-fire model suggested a mechanism explaining these results based on spatiotemporal integration, with fundamental implications relating synchrony to memory encoding.


Chiral recognition in diaziridine clusters and the problem of racemization waves.
Theoretical calculations (B3LYP/6-31+G**) of chiral clusters of diaziridines have been carried out. Five configurations of chiral and nonchiral clusters with up to eight monomers have been considered. The proton transfer within the neutral and protonated clusters has been studied as a possible source of racemization waves. The optical rotatory power (ORP) has been calculated for the neutral and protonated homochiral clusters. The results show that the clusters with alternated chiral molecules are the preferred ones and that the proton transfer proceeds with low energetic barriers in the protonated systems. The ORP results are very dependent on the shape of the clusters and the neutral or protonated state of them.


Knowledge of the residents at King Abdul-Aziz University Hospital (KAAUH) about palliative care.
Palliative care is a rapidly growing subspecialty that aims at improving the quality of life and relieving suffering associated with life threatening disease. Despite its rapid growth and huge demand, the knowledge of health care professionals on palliative care remains inadequate. This study aims to determine the knowledge of residents at King Abdul-Aziz University Hospital (KAAUH) on palliative care. Through a cross-sectional design, all residents in the hospital were invited to complete a two-part self-administered questionnaire in June 2010. The first part of the questionnaire included variables describing the socio-demographic characteristics and educational background, and the second part developed by palliative care education initiative at Dalhousie University in Canada in 2000 had 25 items on the knowledge of palliative care. Of the 80 residents 65 (81%) responded, the overwhelming majority of whom were Saudis (92.3%) with an equal representation of males and females. The mean age of the participants was 29.1 ± 2.4 years. Less than one-third (29.2%) indicated that they had previous didactic education on palliative care. The percentage of right answers on items reflecting knowledge on palliative care accounted for 29.9% ± 9.9%. No statistically significant difference was found in the level of knowledge among the residents according to their demographics or graduation and training characteristics. Resident physicians enrolled in postgraduate programs have suboptimal knowledge of basic palliative care. Substantial efforts should be made to incorporate a palliative care module into the theoretical and practical training of medical students and resident physicians.


A descriptive, cross-sectional study of medical student preferences for vodcast design, format and pedagogical approach.
Vodcasts (video podcasts) are becoming increasingly popular in medical education. At A.T. Still University School of Osteopathic Medicine in Arizona (ATSU SOMA), vodcasts are an essential component of our blended learning environment, where year 2-4 students train in a contextual setting at community health centers across the U.S. Vodcasts are used far less frequently in our year 1 residential learning environment at the main campus in Arizona, but we are considering moving to significantly more interactive educational experiences with on-demand videos followed by in-class activities. The aim of this study was to determine stakeholder (i.e. medical student) preferences for vodcast design, format, and pedagogical strategies. The overall goal was to increase opportunities for students to learn with this modality. An interactive Qualtrics™ survey was administered to three cohorts of medical students. The survey generated quantitative and open-ended response data that addressed principles of vodcast instructional design and learning. Responses to survey items were analyzed for statistical significance using the independent samples t-test for interval data, the chi-square test for categorical data, and the Kruskal-Wallis test for ordinal data, using the post-hoc Bonferroni procedure to determine the appropriate α level. Responses to open-ended prompts were categorized using open- and axial-coding. The most highly valued vodcast attributes, considered essential by all three cohorts, were clear explanations, organization, conciseness, high-yield for medical board exams, and the ability to speed vodcasts up. The least helpful vodcast attributes for all three cohorts were music and objects moving on screen. The average preferred vodcast length for each cohort was 27-28 min. There were significant differences between the less experienced learners in the residential setting and the more mature learners in the blended learning environment regarding certain vodcast attribute preferences, format of included practice questions, explanations for preferred vodcast lengths, and reasons for not viewing vodcasts. Overall, learner preferences were in line with non-interactive, screen-capture type vodcasts, which have lower demands on institutional cost and faculty production time than Flash™-type interactive vodcasts. Students in the blended learning environment were much more focused on vodcast features that decreased their time commitment, including a preference for noninteractive vodcasts. Given the increase in distance learning in medical education, our results should be of value to other medical programs.


Electromagnetic interference of cardiac rhythmic monitoring devices to radio frequency identification: analytical analysis and mitigation methodology.
Increasing density of wireless communication and development of radio frequency identification (RFID) technology in particular have increased the susceptibility of patients equipped with cardiac rhythmic monitoring devices (CRMD) to environmental electro magnetic interference (EMI). Several organizations reported observing CRMD EMI from different sources. This paper focuses on mathematically analyzing the energy as perceived by the implanted device, i.e., voltage. Radio frequency (RF) energy transmitted by RFID interrogators is considered as an example. A simplified front-end equivalent circuit of a CRMD sensing circuitry is proposed for the analysis following extensive black-box testing of several commercial pacemakers and implantable defibrillators. After careful understanding of the mechanics of the CRMD signal processing in identifying the QRS complex of the heart-beat, a mitigation technique is proposed. The mitigation methodology introduced in this paper is logical in approach, simple to implement and is therefore applicable to all wireless communication protocols.


Chemical and Phase Evolution of Amorphous Molybdenum Sulfide Catalysts for Electrochemical Hydrogen Production.
Amorphous MoSx is a highly active, earth-abundant catalyst for the electrochemical hydrogen evolution reaction. Previous studies have revealed that this material initially has a composition of MoS3, but after electrochemical activation, the surface is reduced to form an active phase resembling MoS2 in composition and chemical state. However, structural changes in the MoSx catalyst and the mechanism of the activation process remain poorly understood. In this study, we employ transmission electron microscopy (TEM) to image amorphous MoSx catalysts activated under two hydrogen-rich conditions: ex situ in an electrochemical cell and in situ in an environmental TEM. For the first time, we directly observe the formation of crystalline domains in the MoSx catalyst after both activation procedures as well as spatially localized changes in the chemical state detected via electron energy loss spectroscopy. Using density functional theory calculations, we investigate the mechanisms for this phase transformation and find that the presence of hydrogen is critical for enabling the restructuring process. Our results suggest that the surface of the amorphous MoSx catalyst is dynamic: while the initial catalyst activation forms the primary active surface of amorphous MoS2, continued transformation to the crystalline phase during electrochemical operation could contribute to catalyst deactivation. These results have important implications for the application of this highly active electrocatalyst for sustainable H2 generation.


How antidepressant drugs act: A primer on neuroplasticity as the eventual mediator of antidepressant efficacy.
Depression is conventionally viewed as a state of chemical imbalance, and antidepressants are suggested to act through increasing monoaminergic neurotransmission. These views are currently considered simplistic. This article examines the animal and human literature on the neurohistological mechanisms underlying stress, depression and antidepressant treatment. Pathological stress and depression are associated with changes such as loss of dendritic spines, shrinkage of the dendritic tree and loss of synapses in the hippocampus and prefrontal cortex. There is also a decrease in glia. Apoptosis may occur under extreme circumstances. In contrast, there is increased dendritic arborization and synaptogenesis in the amygdala. Antidepressant treatment protects against and even reverses some but not all of these stress-induced neurohistological changes. Pathological stress results in an aberrant neuroplasticity response characterized by abnormally increased activity in the amygdala and by impaired functioning of the hippocampus, prefrontal cortex and downstream structures. This aberrant neuroplasticity response directly explains most of the clinical symptoms of depression. Antidepressant treatment protects against stress-induced pathoplastic neurohistological and neurocognitive changes. Antidepressant treatment also restores functional neuroplasticity in stressed organisms and, thereby, presumably, facilitates re-adaptation through learning and memory mechanisms. Thus, the stress-depression syndrome and the therapeutic and prophylactic efficacy of antidepressant treatments can be explained through a hardwiring analogy. In this context, glutamate is an important neurotransmitter.


A nonradioactive assay for nitric oxide synthase activity in tissue extracts.
We describe a fluorescence assay for nitric oxide synthase activity based on a new indicator, 4,5-diaminofluorescein (DAF-2). The method offers the advantage of being safer and more convenient than the citrulline radioassay in common use. The rapid and irreversible binding of DAF-2 to oxidized nitric oxide (NO) enables NO production to be measured in real time. The protocol is applied to the measurement of nitric oxide synthase in crude extracts of skeletal muscle.


Extracellular cathepsin K exerts antimicrobial activity and is protective against chronic intestinal inflammation in mice.
Cathepsin K is a lysosomal cysteine protease that has pleiotropic roles in bone resorption, arthritis, atherosclerosis, blood pressure regulation, obesity and cancer. Recently, it was demonstrated that cathepsin K-deficient (Ctsk(-/-) ) mice are less susceptible to experimental autoimmune arthritis and encephalomyelitis, which implies a functional role for cathepsin K in chronic inflammatory responses. Here, the authors address the relevance of cathepsin K in the intestinal immune response during chronic intestinal inflammation. Chronic colitis was induced by administration of 2% dextran sodium sulphate (DSS) in distilled water. Mice were assessed for disease severity, histopathology and endoscopic appearance. Furthermore, DSS-exposed Ctsk(-/-) mice were treated by rectal administration of recombinant cathepsin K. Intestinal microflora was assessed by real-time PCR and 16srDNA molecular fingerprinting of ileal and colonic mucosal and faecal samples. Using Ctsk(-/-) mice, the authors demonstrate a protective role of cathepsin K against chronic DSS colitis. Dissecting the underlying mechanisms the authors found cathepsin K to be present in intestinal goblet cells and the mucin layer. Furthermore, a direct cathepsin K-mediated bactericidal activity against intestinal bacteria was demonstrated, which potentially explains the alteration of intestinal microbiota observed in Ctsk(-/-) mice. Rectal administration of recombinant cathepsin K in DSS-treated Ctsk(-/-) mice ameliorates the severity of intestinal inflammation. These data identify extracellular cathepsin K as an intestinal antibacterial factor with anti-inflammatory potential and suggest that topical administration of cathepsin K might provide a therapeutic option for patients with inflammatory bowel disease.


Genes of the GadX-GadW regulon in Escherichia coli.
Acid in the stomach is thought to be a barrier to bacterial colonization of the intestine. Escherichia coli, however, has three systems for acid resistance, which overcome this barrier. The most effective of these systems is dependent on transport and decarboxylation of glutamate. GadX regulates two genes that encode isoforms of glutamate decarboxylase critical to this system, but additional genes associated with the glutamate-dependent acid resistance system remained to be identified. The gadX gene and a second downstream araC-like transcription factor gene, gadW, were mutated separately and in combination, and the gene expression profiles of the mutants were compared to those of the wild-type strain grown in neutral and acidified media under conditions favoring induction of glutamate-dependent acid resistance. Cluster and principal-component analyses identified 15 GadX-regulated, acid-inducible genes. Reverse transcriptase mapping demonstrated that these genes are organized in 10 operons. Analysis of the strain lacking GadX but possessing GadW confirmed that GadX is a transcriptional activator under acidic growth conditions. Analysis of the strain lacking GadW but possessing GadX indicated that GadW exerts negative control over three GadX target genes. The strain lacking both GadX and GadW was defective in acid induction of most but not all GadX target genes, consistent with the roles of GadW as an inhibitor of GadX-dependent activation of some genes and an activator of other genes. Resistance to acid was decreased under certain conditions in a gadX mutant and even more so by combined mutation of gadX and gadW. However, there was no defect in colonization of the streptomycin-treated mouse model by the gadX mutant in competition with the wild type, and the gadX gadW mutant was a better colonizer than the wild type. Thus, E. coli colonization of the mouse does not appear to require glutamate-dependent acid resistance.


The effects of a strength and neuromuscular exercise programme for the lower extremity on knee load, pain and function in obese children and adolescents: study protocol for a randomised controlled trial.
Childhood obesity is one of the most critical and accelerating health challenges throughout the world. It is a major risk factor for developing varus/valgus misalignments of the knee joint. The combination of misalignment at the knee and excess body mass may result in increased joint stresses and damage to articular cartilage. A training programme, which aims at developing a more neutral alignment of the trunk and lower limbs during movement tasks may be able to reduce knee loading during locomotion. Despite the large number of guidelines for muscle strength training and neuromuscular exercises that exist, most are not specifically designed to target the obese children and adolescent demographic. Therefore, the aim of this study is to evaluate a training programme which combines strength and neuromuscular exercises specifically designed to the needs and limitations of obese children and adolescents and analyse the effects of the training programme from a biomechanical and clinical point of view. A single assessor-blinded, pre-test and post-test randomised controlled trial, with one control and one intervention group will be conducted with 48 boys and girls aged between 10 and 18 years. Intervention group participants will receive a 12-week neuromuscular and quadriceps/hip strength training programme. Three-dimensional (3D) gait analyses during level walking and stair climbing will be performed at baseline and follow-up sessions. The primary outcome parameters for this study will be the overall peak external frontal knee moment and impulse during walking. Secondary outcomes include the subscales of the Knee injury and Osteoarthritis Outcome Score (KOOS), frontal and sagittal kinematics and kinetics for the lower extremities during walking and stair climbing, ratings of change in knee-related well-being, pain and function and adherence to the training programme. In addition, the training programme will be evaulated from a clinical and health status perspective by including the following analyses: cardiopulmonary testing to quantify aerobic fitness effects, anthropometric measures, nutritional status and psychological status to characterise the study sample. The findings will help to determine whether a neuromuscular and strength training exercise programme for the obese children population can reduce joint loading during locomotion, and thereby decrease the possible risk of developing degenerative joint diseases later in adulthood. ClinicalTrials NCT02545764 , Date of registration: 24 September 2015.


Income inequality is associated with stronger social comparison effects: The effect of relative income on life satisfaction.
Previous research has shown that having rich neighbors is associated with reduced levels of subjective well-being, an effect that is likely due to social comparison. The current study examined the role of income inequality as a moderator of this relative income effect. Multilevel analyses were conducted on a sample of more than 1.7 million people from 2,425 counties in the United States. Results showed that higher income inequality was associated with stronger relative income effects. In other words, people were more strongly influenced by the income of their neighbors when income inequality was high.


Multi-modal distraction: insights from children's limited attention.
How does the multi-sensory nature of stimuli influence information processing? Cognitive systems with limited selective attention can elucidate these processes. Six-year-olds, 11-year-olds and 20-year-olds engaged in a visual search task that required them to detect a pre-defined coloured shape under conditions of low or high visual perceptual load. On each trial, a peripheral distractor that could be either compatible or incompatible with the current target colour was presented either visually, auditorily or audiovisually. Unlike unimodal distractors, audiovisual distractors elicited reliable compatibility effects across the two levels of load in adults and in the older children, but high visual load significantly reduced distraction for all children, especially the youngest participants. This study provides the first demonstration that multi-sensory distraction has powerful effects on selective attention: Adults and older children alike allocate attention to potentially relevant information across multiple senses. However, poorer attentional resources can, paradoxically, shield the youngest children from the deleterious effects of multi-sensory distraction. Furthermore, we highlight how developmental research can enrich the understanding of distinct mechanisms controlling adult selective attention in multi-sensory environments.


Healing of implants installed in over- or under-prepared sites--an experimental study in dogs.
To study bone healing at implants installed with different insertion torques. In six Labrador dogs, all mandibular premolars and first molars were extracted. After 4 months of healing, flaps were elevated, and two implant sites were prepared at each side of the mandible. In the right side of the mandible, the distal sites were prepared conventionally, while the mesial sites were over-prepared by 0.2 mm. As a consequence, a final insertion torque of ~30 Ncm at the distal and a minimal insertion torque close to 0 Ncm at the mesial sites were obtained. In the left sides of the mandible, however, the recipient sites were underprepared by 0.3 mm resulting in an insertion torque of ≥ 70 Ncm at both implants. Cover screws were applied, and flaps sutured to fully submerge the experimental sites. After 4 months, the animals were sacrificed and ground sections obtained for histological evaluation. The mineralized bone-to-implant contact was in the range of 55.2-62.1%, displaying the highest value at implants with ~30 Ncm insertion torque and the lowest value at the implant sites with close to 0 Ncm insertion torque. No statistically significant differences were revealed. Bone density was in the range of 43.4-54.9%, yielding the highest value at implants with ≥ 70 Ncm insertion torque and the lowest at the implant sites with close to 0 Ncm insertion torque. The difference between the sites of ~30 Ncm and the corresponding ≥ 70 Ncm insertion torque reached statistical significance. Similar amounts of osseointegration were obtained irrespective of the insertion torque applied. Moreover, implants installed in sites with close to 0 Ncm insertion torque may properly osseointegrate as well.


A review of ultrasonographic methods for the assessment of the anterior cruciate ligament in patients with knee instability - diagnostics using a posterior approach.
The purpose of the study was to improve the ultrasonographic assessment of the anterior cruciate ligament by an inclusion of a dynamic element. The proposed functional modification aims to restore normal posterior cruciate ligament tension, which is associated with a visible change in the ligament shape. This method reduces the risk of an error resulting from subjectively assessing the shape of the posterior cruciate ligament. It should be also emphasized that the method combined with other ultrasound anterior cruciate ligament assessment techniques helps increase diagnostic accuracy. Ultrasonography is used as an adjunctive technique in the diagnosis of anterior cruciate ligament injury. The paper presents a sonographic technique for the assessment of suspected anterior cruciate ligament insufficiency supplemented by the use of a dynamic examination. This technique can be recommended as an additional procedure in routine ultrasound diagnostics of anterior cruciate ligament injuries. Supplementing routine ultrasonography with the dynamic assessment of posterior cruciate ligament shape changes in patients with suspected anterior cruciate ligament injury reduces the risk of subjective errors and increases diagnostic accuracy. This is important especially in cases of minor anterior knee instability and bilateral anterior knee instability. An assessment of changes in posterior cruciate ligament using a dynamic ultrasound examination effectively complements routine sonographic diagnostic techniques for anterior cruciate ligament insufficiency.


[DIFFERENTIATION OF NORM AND PATHOLOGY DURING SELECTIVE BIOCHEMICAL SKREENING OF LYSOSOMAL STORAGE DISEASES WITH INCREASED EXCRETION OF OLIGOSACCHARIDES].
Oligosaccharides are a class of polymeric carbohydrates, which are constituents of a glycoside portion of glycoprotein and glycolipid molecules. The lysosomal hydrolase dysfunction due to lysosomal storage disorders results in partial or complete failure of degradation of some glycoproteins and glycolipids, causing the accumulation of specific undegraded substrates in the lysosomes of cells, the formation of the great number of oligosaccharide chains and their increased excretion with urine. Our work was aimed at detailed study of the specificities of interpreting the results of thin-layer chromatography (TLC) of urine oligosaccharides in healthy persons of different age groups with the purpose of further application of these data while differentiating the norm and pathology in the course of primary selective screening of lysosomal storage disorders. The results obtained demonstrated that TLC plates for the majority of healthy persons had insignificant excretion of a number of oligosaccharides (from monosaccharides to hexasaccharides) with R(lac) > 0.15, which can be characterized as physiological oligosacchariduria, conditioned by the metabolism specificities in lysosomes. Therefore while interpreting the urine samples of patients with the suspected lysosomal storage disorder it is diagnostically reasonable to examine the TLC plates for the presence of both oligosaccharide groups, absent in the samples of healthy persons, and all the fractions with R(lac) < 0.15.


Sensitivity of bacterioplankton nitrogen metabolism to eutrophication in sub-tropical coastal waters of Key West, Florida.
Expression of intracellular ammonium assimilation enzymes were used to assess the response of nitrogen (N) metabolism in bacterioplankton to N-loading of sub-tropical coastal waters of Key West, Florida. Specific activities of glutamine synthetase (GS) and total glutamate dehydrogenase (GDHT) were measured on the bacterial size fraction (<0.8 microm) to assess N-deplete versus N-replete metabolic states, respectively. Enzyme results were compared to concentrations of dissolved organic matter and nutrients and to the biomass and production of phytoplankton and bacteria. Concentrations of dissolved inorganic N (DIN), dissolved organic N (DON), and dissolved organic carbon (DOC) positively correlated with specific activities of GDHT and negatively correlated with that of GS. Total dissolved N (TDN) concentration explained 81% of variance in bacterioplankton GDHT:GS activity ratio. The GDHT:GS ratio, TDN, DOC, and bacterial parameters decreased in magnitude along a tidally dynamic trophic gradient from north of Key West to south at the reef tract, which is consistent with the combined effects of localized coastal eutrophication and tidal exchange of seawater from the Southwest Florida Shelf and Florida Strait. The N-replete bacterioplankton north of Key West can regenerate ammonium which sustains primary production transported south to the reef. The range in GDHT:GS ratios was 5-30 times greater than that for commonly used indicators of planktonic eutrophication, which emphasizes the sensitivity of bacterioplankton N-metabolism to changes in N-bioavailability caused by nutrient pollution in sub-tropical coastal waters and utility of GDHT:GS ratio as an bioindicator of N-replete conditions.


Long-term frequency stabilization of a continuous-wave tunable laser with the help of a precision wavelengthmeter.
For the first time to our knowledge we experimentally demonstrate an efficient method for the reduction of long-term radiation line drift in single-frequency cw Ti:sapphire and dye lasers that relies on a fast and precise wavelengthmeter together with a digital-analog feedback system. Generation line drift of lasers is reduced approximately by an order of magnitude down to 40 MHz/h, which corresponds to the residual drift in readings of the wavelengthmeter itself. The implemented automatic frequency control system allows us to lock the laser generation frequency to a specified absolute value. This approach may be used in single-frequency lasers of different types (solid-state, fiber, diode, dye lasers, etc.) and allows reduction by an order of magnitude or more of the long-term generation line drift in lasers that are not equipped with other systems for long-term stabilization of output radiation frequency.


Acceptability for temporal modification of consecutive segments in isolated words.
Perceptual sensitivity to temporal modification in two consecutive speech segments was measured in word contexts to explore the following two questions: (1) whether there is an interaction between multiple segmental durations, and (2) what aspect of the stimulus context determines the perceptually salient temporal markers? Experiment 1 obtained acceptability ratings for words with temporal modifications. The results showed that the compensatory change in duration of a vowel (V) and its adjacent consonant (C) is not perceptually so salient as expected for the simultaneous modifications in the two segments. This finding suggests the presence of a time perception range wider than a single segment (V or C). The results of experiment 1 also showed that rating scores for compensatory modification between V and C do not depend on the temporal order of modified pairs (VC or CV), but rather on the loudness difference between V and C; the acceptability decreased when the loudness difference between V and C became high. This suggests that perceptually salient markers locate around major jumps in loudness. The second finding, the dependence on the loudness jump, was replicated in experiment 2, which utilized a detection task for temporal modifications on nonspeech stimuli modeling the time-loudness features of the speech stimuli. Experiment 3 further investigated the influence of the temporal order of V and C by utilizing the detection task for the speech stimuli instead of the acceptability ratings.


Absence of Intraocular Lymphatic Vessels in Uveal Melanomas with Extrascleral Growth.
The aim of this study was to investigate the presence of intraocular lymphatic vessels in patients with uveal melanomas and extrascleral extension using a panel of lymphatic markers. The following immunohistochemical markers were analyzed: lymphatic vessel endothelial hyaluronic acid receptor-1 (LYVE-1), podoplanin (D2-40), prospero-related homeobox gene-1 (Prox-1), pan-endothelial marker cluster of differentiation 31 (CD31), and blood vessel endothelium-specific CD34. Lymphatic vessels were defined as a combination of staining of the following positive markers: LYVE-1, D2-40, Prox-1, and CD31; and no staining of the negative marker CD34. In total, 456 patients were enucleated; 16 of the 46 uveal melanomas with extrascleral extension were contained in stored paraffin tissue. Two samples of the 16 uveal melanomas showed focal positive intraocular vascular staining for LYVE-1 and co-expression of CD31 and CD34. Due to the lack of Prox-1 and D2-40, and positive expression of CD34, these cannot be classified as lymphatic vessels. In one case recruitment of an extraocular, intratumoral lymphatic vascular structure was observed in the periphery of the subconjunctival extrascleral extension. Intraocular lymphatic vessels are absent in uveal melanomas with extrascleral extension; however, we provide proof for recruitment of intratumoral lymphatics by uveal melanomas with extraocular extension from subconjunctival lymphatics that may explain the rare cases of regional lymphatic spread. A panel of antibodies is necessary to detect lymphatic vessels with high specificity.


Rhodiola rosea Exerts Antiviral Activity in Athletes Following a Competitive Marathon Race.
Rhodiola rosea, a medicinal plant with demonstrated adaptogenic properties, has recently been reported to contain active compounds with antimicrobial activity. The goal of this study was to measure the antiviral and antibacterial properties of the bioactive metabolites of Rhodiola rosea in the serum of experienced marathon runners following supplementation. Marathon runners, randomly divided into two groups, ingested 600 mg/day of Rhodiola rosea (n = 24, 6 female, 18 male) or placebo (n = 24, 7 females, 17 males) for 30 days prior to, the day of, and 7 days post-marathon. Blood serum samples were collected the day before, 15 min post-, and 1.5 h post-marathon. Serum from Rhodiola rosea-supplemented runners collected after marathon running did not attenuate the marathon-induced susceptibility of HeLa cells to killing by vesicular stomatitis virus. However, the use of Rhodiola rosea induced antiviral activity at early times post-infection by delaying an exercise-dependent increase in virus replication (P = 0.013 compared to placebo). Serum from both groups collected 15 min post-marathon significantly promoted the growth of Escherichia coli in culture as compared to serum collected the day before the marathon (P = 0.003, all subjects). Furthermore, the serum from subjects ingesting Rhodiola rosea did not display antibacterial properties at any time point as indicated by a lack of group differences immediately (P = 0.785) or 1.5 h (P = 0.633) post-marathon. These results indicate that bioactive compounds in the serum of subjects ingesting Rhodiola rosea may exert protective effects against virus replication following intense and prolonged exercise by inducing antiviral activity.


Identifying and integrating patient and caregiver perspectives for clinical practice guidelines on the screening and management of infectious microorganisms in hemodialysis units.
The integration of patient and caregiver input into guideline development can help to ensure that clinical care addresses patient expectations, priorities, and needs. We aimed to identify topics and outcomes salient to patients and caregivers for inclusion in the Kidney Health Australia Caring for Australasians with Renal Impairment (KHA-CARI) clinical practice guideline on the screening and management of infectious microorganisms in hemodialysis units. A facilitated workshop was conducted with 11 participants (patients [n = 8], caregivers [n = 3]). Participants identified and discussed potential topics for inclusion in the guidelines, which were compared to those developed by the guideline working group. The workshop transcript was thematically analyzed to identify and describe the reasons underpinning their priorities. Patients and caregivers identified a range of topics already covered by the scope of the proposed guidelines and also suggested additional topics: privacy and confidentiality, psychosocial care during/after disease notification, quality of transportation, psychosocial treatment of patients in isolation, patient/caregiver education and engagement, and patient advocacy. Five themes characterized discussion and underpinned their choices: shock and vulnerability, burden of isolation, fear of infection, respect for privacy and confidentiality, and confusion over procedural inconsistencies. Patients and caregivers emphasized the need for guidelines to address patient education and engagement, and the psychosocial implications of communication and provision of care in the context of infectious microorganisms in hemodialysis units. Integrating patient and caregiver perspectives can help to improve the relevance of guidelines to enhance quality of care, patient experiences, and health and psychosocial outcomes.


A Qualitative Study of the Views of Patients With Medically Unexplained Symptoms on The BodyMind Approach®: Employing Embodied Methods and Arts Practices for Self-Management.
The arts provide openings for symbolic expression by engaging the sensory experience in the body they become a source of insight through embodied cognition and emotion, enabling meaning-making, and acting as a catalyst for change. This synthesis of sensation and enactive, embodied expression through movement and the arts is capitalized on in The BodyMind Approach® (TBMA). It is integral to this biopsychosocial, innovative, unique intervention for people suffering medically unexplained symptoms (MUS) applied in primary healthcare. The relevance of embodiment and arts practices in TBMA are discussed in relation to the views of participants in the pursuit of self-management. If widely employed TBMA could have an enormous impact, reach, and significance for patients and global health services. This original pre-clinical trial of qualitative research reports on the perceptions of participant patients with generic MUS, a world-wide issue usually treated by either psychological therapy or physiotherapy. TBMA is not a therapy but a health education program founded upon the concept of an integration of psychological elements with physiological, bodily, and sensory experiences. Thematic analysis of qualitative data sets from open-ended questions in semi-structured interviews and a written questionnaire post intervention is presented. Five aspects which appear to be key to learning self-management were derived from analyzing the data: (1) body with mind connections; (2) importance of facilitation; (3) potential benefits; (4) preparedness for change; (5) self-acceptance/compassion. This article advances the discourse on the nature of self-management for MUS through changing the mind-set and the relationship participants have with their bodily symptom/s through employing embodied methods and arts practices, challenging current, and solely verbal, psychological conceptual frameworks. Rigor lies in the method of data analysis using cross verification of credibility between reported findings and scrutiny by stakeholders. We conclude that facilitated TBMA groups employing embodied methods and arts practices can act as a method for developing the self-management of MUS and improving wellbeing.


Adenine nucleoside diphosphates block adaptation of mechanoelectrical transduction in hair cells.
By adapting to sustained stimuli, hair cells in the internal ear retain their sensitivity to minute transient displacements. Because one model for adaptation asserts that this process is mediated by a myosin isozyme, we reasoned that we should be able to arrest adaptation by interfering with myosin's ATPase cycle though introduction of ADP into hair cells. During tight-seal, whole-cell recordings of transduction currents in cells isolated from bullfrog (Rana catesbeiana) sacculus, dialysis with 5-25 mM ADP gave variable results. In half of the cells examined, the rate of adaptation remained unchanged or even increased; adaptation was blocked in the remaining cells. Because we suspected that the variable effect of ADP resulted from the conversion of ADP to ATP by adenylate kinase, we employed the ADP analog adenosine 5'-[beta-thio]diphosphate (ADP[beta S]), which is not a substrate for adenylate kinase. Adaptation consistently disappeared in the presence of 1-10 mM ADP[beta S]; in addition, the transduction channels' open probability at rest grew from approximately 0.1 to 0.8 or more. Both effects could be reversed by 2 mM ATP. When used in conjunction with the adenylate kinase inhibitor P1,P5-bis(5'-adenosyl) pentaphosphate (Ap5A), ADP had effects similar to those of ADP[beta S]. These results suggest that adaptation by hair cells involves adenine nucleotides, and they lend support to the hypothesis that the adaptation process is powered by a myosin motor.


Long-term exposure to fluoxetine reduces growth and reproductive potential in the dominant rocky intertidal mussel, Mytilus californianus.
Environmental stressors shape community composition and ecosystem functioning. Contaminants such as pharmaceuticals are of increasing concern as an environmental stressor due to their persistence in surface waters worldwide. Limited attention has been paid to the effects of pharmaceuticals on marine life, despite widespread detection of these contaminants in the marine environment. Of the existing studies, the majority assess the negative effects of pharmaceuticals over an exposure period of 30 days or less and focus on cellular and subcellular biomarkers. Longer studies are required to determine if chronic contaminant exposure poses risks to marine life at environmentally relevant concentrations; and examination of whole organism effects are necessary to identify potential community-level consequences in estuarine and marine ecosystems. We conducted a long-term exposure study (107 days) with the anti-depressant pharmaceutical, fluoxetine (the active constituent in Prozac®) to determine whether minimal concentrations affected whole organism metrics in the California mussel, Mytilus californianus. We measured algal clearance rates, mussel growth, and the gonadosomatic index, a measure of reproductive health. We found that fluoxetine negatively affects all measured characteristics, however many effects were mediated by length of exposure. Our results fill an important data gap, highlighting organism-level effects of chronic exposure periods; such data more explicitly identify the overall impacts of pharmaceuticals and other contaminants on marine communities and ecosystems.


Vegan supplemented diet in nephrotic syndrome.
Thirteen patients (7 males, 6 females, aged 17-68 years) affected by primary, steroid-resistant, nephrotic syndrome and normal renal function were treated with a vegan, low-protein (0.7 g/kg per day) diet supplemented with essential amino acids and Ketoanalogues (VSD) for 3.9 +/- 2.9 months. These patients were studied at the beginning (following an unrestricted protein diet (UPD) supplying about 1 g/kg per day of mixed proteins) and at the end of VSD period. Urinary protein excretion decreased from 8.7 +/- 2.6 to 5.6 +/- 2.4 g/day (P less than 0.01), serum total cholesterol from 334.6 +/- 97.1 to 275.6 +/- 49.4 mg/dl (P less than 0.05). Serum albumin, HDL-cholesterol, triglycerides, and anthropometric measurements (triceps skinfold thickness and middle arm muscle circumference) did not change. Urinary urea nitrogen decreased from 7.5 +/- 1.8 to 3.8 +/- 1.2 g/day (P less than 0.005), according to dietary prescriptions. Creatinine clearance changed from 104.4 +/- 28.7 to 89.3 +/- 16.7 ml/min (n.s.) and no correlation was found with the changes in urinary protein excretion. This data suggest that VSD reduces proteinuria and exerts favourable effects on hypercholesterolaemia. Protein malnutrition was absent in these patients, probably because of the essential amino acids and ketoanalogues supplementation.


Virulence determinants in clinical Staphylococcus aureus from monomicrobial and polymicrobial infections of diabetic foot ulcers.
Antibiotic resistance in Staphylococcus aureus is a major public health concern, and methicillin-resistant S. aureus has emerged as an important pathogen. We characterized S. aureus isolates from monomicrobial and polymicrobial wound infections from 200 diabetic individuals with foot ulcers to understand their underlying diversity and pathogenicity. Staphylococcal cassette chromosome mec typing was performed, and genes coding for production of biofilm, Panton-Valentine leukocidin, toxic shock syndrome toxin and leukotoxins DE and M were screened. Biofilm production was also quantified by the tissue culture plate method. Strains were genotyped using multilocus sequence typing, multiple-locus variable number tandem repeat analysis and repetitive sequence PCR methods. Polymicrobial infections were present in 115 samples, 61 samples showed monomicrobial infection and 24 samples were culture negative. Polymicrobial infections were significantly higher in patients with previous amputation history. Of the 86 samples infected with S. aureus, virulence genes were found in 81 isolates, and 41 isolates possessed more than one virulence gene. Strains which contained pvl gene alone or luk-DE alone were significantly higher in polymicrobial wounds. Based on biofilm production, 18.6 % of isolates were classified as high, 24.4 % as moderate and 57 % as low biofilm producers. Genotyping of 30 strains revealed 10 different sequence types with a strong association among sequence types, specific virulence markers and antibiotic resistance profiles. Moreover, isolates from monomicrobial and polymicrobial wounds differed significantly in their virulence potential and the sequence types to which they belonged, and these are helpful in mapping the evolution of the identified strains of S. aureus.


Petri dish PCR: laser-heated reactions in nanoliter droplet arrays.
We report high-speed real-time PCR performed on an unmodified disposable polystyrene Petri dish. The reaction cycle relies solely on an infrared laser for heating; no conventional heater is required. Nanoliter droplets of PCR mixture as water-in-oil emulsions printed in an array format served as individual PCR microreactors. A simple contact printing technique was developed to generate a large array of uniform sized nanoliter droplets using disposable pipette tips. Printed droplets showed variation of less than 10% in volume and the oil/water/polystyrene interface formed a compact droplet microreactor approximately spherical in shape. The uniform droplet array was used to optimize the laser power required for the two heating steps of PCR, annealing/extension and melting, while the ambient conditions were at room temperature. The optical heating allows for an extremely fast heating rate due to the selective absorption of the infrared laser by PCR buffer only and not the oil or polystyrene Petri dish, allowing completion of 40 amplification cycles in approximately 6 minutes. The quantitative assay capability of the system is also presented and discussed.


Association of oxidative status and semen characteristics with seminal plasma proteins of buffalo semen.
To study the influence of season on oxidative status of buffalo semen and their association with semen characteristics and seminal plasma proteins, ejaculates were collected twice a week in winter, summer and rainy seasons from six adult Bhadawari buffalo bulls. The neat semen was analyzed for semen characteristics immediately after collection and oxidative status viz. lipid peroxidation (LPO), catalase (CAT), super oxide dismutase (SOD) activity, and total protein (TP) were estimated in seminal plasma. The protein profiling was carried out by one-dimensional sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). The significant effect of season was observed on TP, SOD activity and % protein fractions of seminal plasma proteins of buffalo bulls. The TP values showed positive correlation with ejaculate volume (EV), sperm concentration (SC), and % live-dead (LD) and negative correlation with progressive motility (PM), and hypo-osmotic swelling test (HOST). The SOD activity showed positive correlation with PM, LD, HOST and % acrosoamal integrity (AI). Besides that, results showed correlation of TP with 6.5, 38 and 66 kDa proteins, LPO with 70, 72, 84 and 86 kDa proteins, CAT with 70 kDa and 86 kDa proteins, and SOD with 6.5, 24.5, 44.5, 70 and 72 kDa proteins. In conclusion, this study indicated that TP and SOD activity of seminal plasma of buffalo bulls were influenced by season and were found to be associated with some of the semen characteristics and expression of seminal plasma proteins.


Divergent patterns of progression to AIDS after infection from the same source: human immunodeficiency virus type 1 evolution and antiviral responses.
The rate of progression to AIDS in human immunodeficiency virus type 1 (HIV-1)-infected individuals is determined by a complex series of interactions between the host and virus. Here we evaluate virologic properties and host responses in two men near-simultaneously infected with HIV-1 from the same sexual partner--one individual progressed to AIDS in less than 2 years, and the other remains asymptomatic 3 years postinfection. Distinct neutralizing antibody and cellular immune responses were evident, with the slower progressor exhibiting generally stronger and broader responses, except for cytotoxic T-lymphocyte responses early in infection. Virtually identical, homogeneous virus populations were found in both patients in the first sample obtained; however, a second unrelated HIV-1 virus population was also found in the fast progressor. Whether the second population emanated from an additional source of infection or the two were transmitted from the original source could not be determined. The virus population in the slower progressor turned over and diversified rapidly, whereas both virus populations in the rapid progressor evolved at a much slower rate. In addition, the character of mutational changes underlying these diversities appeared to be distinct, with a bias for diversifying selection developing in the slower progressor and a reciprocal bias towards purifying selection maintained in both populations in the fast progressor. Thus, the rapid evolution that is a hallmark of HIV replication may be a reflection of strong host resistance against emerging virus variants and a longer period of asymptomatic infection. Furthermore, rapid progression was not linked to a collapse of any appreciable immune response following attainment of some threshold of antigenic diversity but rather to a failure to drive this diversification and a condition of relatively unimpeded expansion of variants with optimized replicative capacity within the host.


Diversiform Nanostructures Constructed from Tetraphenylethene and Pyrene-Based Acid/Base Controllable Molecular Switching Amphiphilic [2]Rotaxanes with Tunable Aggregation-Induced Static Excimers.
Dual-emissive tetraphenylethene (TPE) and pyrene-containing amphiphilic molecules are of great interest because they can be integrated to form stimuli responsive materials with various biological applications. Herein, we report the study of mechanically interlocked molecules (MIMs) with aggregation-induced static excimer emission (AISEE) property through a series of TPE and pyrene-based amphiphilic [2]rotaxanes, where t-butylcalix[4]arene with hydrophobic nature was used as the macrocycle. Evidently, by adorning TPE and pyrene units in [2]rotaxanes P1, P2, P1-b, and P2-b, they display remarkable emission bands in 70% of water fraction (fw) in tetrahydrofuran (THF)/water mixture, which could be attributed to the restricted intramolecular rotation of phenyl groups, whereas prominent blue-shifted excimer emission of pyrene started to appear as fw reached 80% for P1 and 90% for P1-b, P2, and P2-b, which was ascribed to the favorable π-π stacking and hydrophobic interactions of the pyrene rings that enabled their static excimer formation. The well-defined distinct amphiphilic nanostructures of [2]rotaxanes including hollowspheres, mesoporous nanostructures, spheres, and network linkages can be driven smoothly depending on the molecular structures and their aggregated states in THF/water mixture. These fascinating diversiform nanostructures were mainly controlled by the skillful manner of reversible molecular shuttling of t-butylcalix[4]arene macrocycle and also the interplay of multinoncovalent interactions. To further understand the aggregation capabilities of [2]rotaxanes, the human lung fibroblasts (MRC-5) living cell incubated with either P1, P2, P1-b, or P2-b was studied and monitored by confocal laser scanning microscopy. The AISEE property was achieved at an astonishing level by integrating TPE and pyrene to MIM-based reversible molecular switching [2]rotaxanes; furthermore, distinct nanostructures, especially hollowspheres and mesoporous nanostructures, were observed, which are rarely reported in the literature but are highly desirable for future applications.


Towards an integrated morphological and molecular WHO diagnosis of central nervous system tumors: a paradigm shift.
It is now fully clear that information on the molecular underpinnings of tumors of the central nervous system (CNS) can be used for a more robust characterization of at least selected neoplasms. During a meeting organized in Haarlem, The Netherlands, in May 2014, about 30 neuropathologists discussed how exactly molecular information could be incorporated in the routine classification of CNS tumors. This meeting laid the groundwork for an update of the WHO CNS tumor classification that integrates histopathological and molecular findings. Furthermore, a layered diagnostic approach was proposed that not only allows for integration of relevant molecular information in the pathological diagnosis, but also retains the option for rendering a diagnosis based on histopathological analysis alone. An integrated morphological and molecular definition of CNS tumors brings new challenges as well. For example, criteria for grading within molecularly defined categories of diffuse gliomas will require modification, and some tests used in clinical practice for the detection of molecular features, may provide false positive or false negative results. The evolving paradigm shift represents a major leap forward in the diagnosis of CNS tumors that will contribute substantially to optimizing interobserver reproducibility and clinico-pathological predictions.


Singular perturbation analysis of competitive neural networks with different time scales.
The dynamics of complex neural networks must include the aspects of long- and short-term memory. The behavior of the network is characterized by an equation of neural activity as a fast phenomenon and an equation of synaptic modification as a slow part of the neural system. The main idea of this paper is to apply a stability analysis method of fixed points of the combined activity and weight dynamics for a special class of competitive neural networks. We present a quadratic-type Lyapunov function for the flow of a competitive neural system with fast and slow dynamic variables as a global stability method and a modality of detecting the local stability behavior around individual equilibrium points.


Endothelial vasodilator production by uterine and systemic arteries. I. Effects of ANG II on PGI2 and NO in pregnancy.
Uterine vasculature is less responsive than systemic vasculature to angiotensin II (ANG II)-induced vasoconstriction. We hypothesized that pregnancy augments basal and ANG II-stimulated endothelial prostacyclin (PGI2) and/or nitric oxide (NO) production, which locally increase vascular smooth muscle (VSM) adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP), respectively. Uterine (UA) and systemic arteries (SA) from pregnant (P) and nonpregnant (NP) sheep were incubated with isobutylmethylxanthine. Basal PGI2, cAMP, and cGMP production was 2.4-, 1.6-, and 5.9-fold greater (P < 0.01) in UA from P vs. NP sheep; endothelium removal lowered (P < 0.05) values 69, 44, and 88%. Basal SA PGI2 and cAMP, but not cGMP, also were elevated by pregnancy. Indomethacin (Indo; 100 microM) decreased PGI2 and cAMP, but not cGMP production; N omega-nitro-L-arginine methyl ester (L-NAME; 10 microM) and methylene blue (MB, 10 microM) only decreased cGMP. Basal UA, but not SA, NO synthase activity (conversion of [3H]arginine to [3H]citrulline), was 1.8-fold higher in pregnancy and decreased (P < 0.01) after endothelium removal and with L-NAME. ANG II (50 nM) increased PGI2 (86%) and cAMP (56%) production only in UA from P sheep (P < 0.05); this was abolished by endothelium removal or Indo. ANG II also increased (P < 0.01) cGMP production by UA from both groups but only by SA from P ewes; this was absent in denuded, L-NAME-, or MB-treated vessels. Stimulation of VSM cGMP production with sodium nitroprusside (50 microM) was inhibited by MB, but not L-NAME or endothelium removal. In pregnancy, endothelial PGI2 and NO production are enhanced and may contribute to attenuated ANG II vasoconstriction via VSM cAMP and cGMP.


Crossword expertise as recognitional decision making: an artificial intelligence approach.
THE SKILLS REQUIRED TO SOLVE CROSSWORD PUZZLES INVOLVE TWO IMPORTANT ASPECTS OF LEXICAL MEMORY: semantic information in the form of clues that indicate the meaning of the answer, and orthographic patterns that constrain the possibilities but may also provide hints to possible answers. Mueller and Thanasuan (2013) proposed a model accounting for the simple memory access processes involved in solving individual crossword clues, but expert solvers also bring additional skills and strategies to bear on solving complete puzzles. In this paper, we developed an computational model of crossword solving that incorporates strategic and other factors, and is capable of solving crossword puzzles in a human-like fashion, in order to understand the complete set of skills needed to solve a crossword puzzle. We compare our models to human expert and novice solvers to investigate how different strategic and structural factors in crossword play impact overall performance. Results reveal that expert crossword solving relies heavily on fluent semantic memory search and retrieval, which appear to allow experts to take better advantage of orthographic-route solutions, and experts employ strategies that enable them to use orthographic information. Furthermore, other processes central to traditional AI models (error correction and backtracking) appear to be of less importance for human players.


Mind (is) your body.
The majority of people who experience mental health issues also have poor physical health resulting in decreased life expectancy. Fortunately, many physical health issues can be identified and rectified by monitoring various health indicators over a time period. The Physical Health Diary is a tool that people can use by themselves and/or with others to track, monitor and improve their physical health over time.


Tumor-on-chip modeling of organ-specific cancer and metastasis.
Every year, cancer claims millions of lives around the globe. Unfortunately, model systems that accurately mimic human oncology - a requirement for the development of more effective therapies for these patients - remain elusive. Tumor development is an organ-specific process that involves modification of existing tissue features, recruitment of other cell types, and eventual metastasis to distant organs. Recently, tissue engineered microfluidic devices have emerged as a powerful in vitro tool to model human physiology and pathology with organ-specificity. These organ-on-chip platforms consist of cells cultured in 3D hydrogels and offer precise control over geometry, biological components, and physiochemical properties. Here, we review progress towards organ-specific microfluidic models of the primary and metastatic tumor microenvironments. Despite the field's infancy, these tumor-on-chip models have enabled discoveries about cancer immunobiology and response to therapy. Future work should focus on the development of autologous or multi-organ systems and inclusion of the immune system.


ALS/FTD mutations in UBQLN2 impede autophagy by reducing autophagosome acidification through loss of function.
Mutations in UBQLN2 cause amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerations. However, the mechanism by which the UBQLN2 mutations cause disease remains unclear. Alterations in proteins involved in autophagy are prominent in neuronal tissue of human ALS UBQLN2 patients and in a transgenic P497S UBQLN2 mouse model of ALS/FTD, suggesting a pathogenic link. Here, we show UBQLN2 functions in autophagy and that ALS/FTD mutant proteins compromise this function. Inactivation of UBQLN2 expression in HeLa cells reduced autophagic flux and autophagosome acidification. The defect in acidification was rescued by reexpression of wild type (WT) UBQLN2 but not by any of the five different UBQLN2 ALS/FTD mutants tested. Proteomic analysis and immunoblot studies revealed P497S mutant mice and UBQLN2 knockout HeLa and NSC34 cells have reduced expression of ATP6v1g1, a critical subunit of the vacuolar ATPase (V-ATPase) pump. Knockout of UBQLN2 expression in HeLa cells decreased turnover of ATP6v1g1, while overexpression of WT UBQLN2 increased biogenesis of ATP6v1g1 compared with P497S mutant UBQLN2 protein. In vitro interaction studies showed that ATP6v1g1 binds more strongly to WT UBQLN2 than to ALS/FTD mutant UBQLN2 proteins. Intriguingly, overexpression of ATP6v1g1 in UBQLN2 knockout HeLa cells increased autophagosome acidification, suggesting a therapeutic approach to overcome the acidification defect. Taken together, our findings suggest that UBQLN2 mutations drive pathogenesis through a dominant-negative loss-of-function mechanism in autophagy and that UBQLN2 functions as an important regulator of the expression and stability of ATP6v1g1. These findings may have important implications for devising therapies to treat UBQLN2-linked ALS/FTD.


Characterizing monoclonal antibody structure by carbodiimide/GEE footprinting.
Amino acid-specific covalent labeling is well suited to probe protein structure and macromolecular interactions, especially for macromolecules and their complexes that are difficult to examine by alternative means, due to size, complexity, or instability. Here we present a detailed account of carbodiimide-based covalent labeling (with GEE tagging) applied to a glycosylated monoclonal antibody therapeutic, which represents an important class of biologic drugs. Characterization of such proteins and their antigen complexes is essential to development of new biologic-based medicines. In this study, the experiments were optimized to preserve the structural integrity of the protein, and experimental conditions were varied and replicated to establish the reproducibility and precision of the technique. Homology-based models were generated and used to compare the solvent accessibility of the labeled residues, which include D, E, and the C-terminus, against the experimental surface accessibility data in order to understand the accuracy of the approach in providing an unbiased assessment of structure. Data from the protein were also compared to reactivity measures of several model peptides to explain sequence or structure-based variations in reactivity. The results highlight several advantages of this approach. These include: the ease of use at the bench top, the linearity of the dose response plots at high levels of labeling (indicating that the label does not significantly perturb the structure of the protein), the high reproducibility of replicate experiments (<2 % variation in modification extent), the similar reactivity of the 3 target probe residues (as suggested by analysis of model peptides), and the overall positive and significant correlation of reactivity and solvent accessible surface area (the latter values predicted by the homology modeling). Attenuation of reactivity, in otherwise solvent accessible probes, is documented as arising from the effects of positive charge or bond formation between adjacent amine and carboxyl groups, the latter accompanied by observed water loss. The results are also compared with data from hydroxyl radical-mediated oxidative footprinting on the same protein, showing that complementary information is gained from the 2 approaches, although the number of target residues in carbodiimide/GEE labeling is fewer. Overall, this approach is an accurate and precise method for assessing protein structure of biologic drugs.


Chronic exposure to staphylococcal superantigen elicits a systemic inflammatory disease mimicking lupus.
Chronic nasal and skin colonization with superantigen (SAg)-producing Staphylococcus aureus is well documented in humans. Given that trans-mucosal and trans-cutaneous absorption of SAgs can occur, we determined whether chronic exposure to small amounts of SAg per se could activate autoreactive CD4(+) and CD8(+) T cells and precipitate any autoimmune disease without further external autoantigenic stimulation. Because HLA class II molecules present SAg more efficiently than do mouse MHC class II molecules, HLA-DQ8 transgenic mice were implanted s.c. with mini-osmotic pumps capable of continuously delivering the SAg, staphylococcal enterotoxin B (total of 10 μg/mouse), or PBS over 4 wk. Chronic exposure to staphylococcal enterotoxin B resulted in a multisystem autoimmune inflammatory disease with features similar to systemic lupus erythematosus. The disease was characterized by mononuclear cell infiltration of lungs, liver, and kidneys, accompanied by the production of anti-nuclear Abs and deposition of immune complexes in the renal glomeruli. The inflammatory infiltrates in various organs predominantly consisted of CD4(+) T cells bearing TCR Vβ8. The extent of immunopathology was markedly reduced in mice lacking CD4(+) T cells and CD28, indicating that the disease is CD4(+) T cell mediated and CD28 dependent. The absence of disease in STAT4-deficient, as well as IFN-γ-deficient, HLA-DQ8 mice suggested the pathogenic role of Th1-type cytokines, IL-12 and IFN-γ. In conclusion, our study suggests that chronic exposure to extremely small amounts of bacterial SAg could be an etiological factor for systemic lupus erythematosus.


Effects of rapamycin on cultured hepatocyte proliferation and gene expression.
Rapamycin, a potent immunosuppressive drug that disrupts normal signal-transduction processes, inhibited hepatocyte proliferation without evidence of inherent cytotoxicity in rat hepatocytes cultured in conventional medium or in a medium enriched with epidermal growth factor. The antiproliferative effect was dose dependent, uninfluenced by the concentration of epidermal growth factor in the medium and long lasting after a brief exposure. The effect of rapamycin was unaltered by the concomitant presence of FK 506 in the medium, suggesting that different binding affinities of these two drugs or even a separate rapamycin binding site may exist. Hepatocytes harvested 12 and 24 hr after partial hepatectomy were progressively less responsive to the antiproliferative effect of rapamycin. The gene expression of transforming growth factor-beta was reduced under in vivo rapamycin treatment, but at the same time the gene expression of albumin and glyceraldehyde-3-phosphate dehydrogenase was unchanged or increased. The experiments confirm that rapamycin has inherent growth-control qualities, and they strengthen the hypothesis that the recently defined immunophilin network is central to many aspects of cellular growth control.


Y-chromosome analysis in individuals bearing the Basarab name of the first dynasty of Wallachian kings.
Vlad III The Impaler, also known as Dracula, descended from the dynasty of Basarab, the first rulers of independent Wallachia, in present Romania. Whether this dynasty is of Cuman (an admixed Turkic people that reached Wallachia from the East in the 11(th) century) or of local Romanian (Vlach) origin is debated among historians. Earlier studies have demonstrated the value of investigating the Y chromosome of men bearing a historical name, in order to identify their genetic origin. We sampled 29 Romanian men carrying the surname Basarab, in addition to four Romanian populations (from counties Dolj, N = 38; Mehedinti, N = 11; Cluj, N = 50; and Brasov, N = 50), and compared the data with the surrounding populations. We typed 131 SNPs and 19 STRs in the non-recombinant part of the Y-chromosome in all the individuals. We computed a PCA to situate the Basarab individuals in the context of Romania and its neighboring populations. Different Y-chromosome haplogroups were found within the individuals bearing the Basarab name. All haplogroups are common in Romania and other Central and Eastern European populations. In a PCA, the Basarab group clusters within other Romanian populations. We found several clusters of Basarab individuals having a common ancestor within the period of the last 600 years. The diversity of haplogroups found shows that not all individuals carrying the surname Basarab can be direct biological descendants of the Basarab dynasty. The absence of Eastern Asian lineages in the Basarab men can be interpreted as a lack of evidence for a Cuman origin of the Basarab dynasty, although it cannot be positively ruled out. It can be therefore concluded that the Basarab dynasty was successful in spreading its name beyond the spread of its genes.


Tape underlayment rotary-node (TURN) valves for simple on-chip microfluidic flow control.
We describe a simple and reliable fabrication method for producing multiple, manually activated microfluidic control valves in polydimethylsiloxane (PDMS) devices. These screwdriver-actuated valves reside directly on the microfluidic chip and can provide both simple on/off operation as well as graded control of fluid flow. The fabrication procedure can be easily implemented in any soft lithography lab and requires only two specialized tools-a hot-glue gun and a machined brass mold. To facilitate use in multi-valve fluidic systems, the mold is designed to produce a linear tape that contains a series of plastic rotary nodes with small stainless steel machine screws that form individual valves which can be easily separated for applications when only single valves are required. The tape and its valves are placed on the surface of a partially cured thin PDMS microchannel device while the PDMS is still on the soft-lithographic master, with the master providing alignment marks for the tape. The tape is permanently affixed to the microchannel device by pouring an over-layer of PDMS, to form a full-thickness device with the tape as an enclosed underlayment. The advantages of these Tape Underlayment Rotary-Node (TURN) valves include parallel fabrication of multiple valves, low risk of damaging a microfluidic device during valve installation, high torque, elimination of stripped threads, the capabilities of TURN hydraulic actuators, and facile customization of TURN molds. We have utilized these valves to control microfluidic flow, to control the onset of molecular diffusion, and to manipulate channel connectivity. Practical applications of TURN valves include control of loading and chemokine release in chemotaxis assay devices, flow in microfluidic bioreactors, and channel connectivity in microfluidic devices intended to study competition and predator/prey relationships among microbes.


RuleMonkey: software for stochastic simulation of rule-based models.
The system-level dynamics of many molecular interactions, particularly protein-protein interactions, can be conveniently represented using reaction rules, which can be specified using model-specification languages, such as the BioNetGen language (BNGL). A set of rules implicitly defines a (bio)chemical reaction network. The reaction network implied by a set of rules is often very large, and as a result, generation of the network implied by rules tends to be computationally expensive. Moreover, the cost of many commonly used methods for simulating network dynamics is a function of network size. Together these factors have limited application of the rule-based modeling approach. Recently, several methods for simulating rule-based models have been developed that avoid the expensive step of network generation. The cost of these "network-free" simulation methods is independent of the number of reactions implied by rules. Software implementing such methods is now needed for the simulation and analysis of rule-based models of biochemical systems. Here, we present a software tool called RuleMonkey, which implements a network-free method for simulation of rule-based models that is similar to Gillespie's method. The method is suitable for rule-based models that can be encoded in BNGL, including models with rules that have global application conditions, such as rules for intramolecular association reactions. In addition, the method is rejection free, unlike other network-free methods that introduce null events, i.e., steps in the simulation procedure that do not change the state of the reaction system being simulated. We verify that RuleMonkey produces correct simulation results, and we compare its performance against DYNSTOC, another BNGL-compliant tool for network-free simulation of rule-based models. We also compare RuleMonkey against problem-specific codes implementing network-free simulation methods. RuleMonkey enables the simulation of rule-based models for which the underlying reaction networks are large. It is typically faster than DYNSTOC for benchmark problems that we have examined. RuleMonkey is freely available as a stand-alone application http://public.tgen.org/rulemonkey. It is also available as a simulation engine within GetBonNie, a web-based environment for building, analyzing and sharing rule-based models.


Transforaminal Lumbar Interbody Fusion: Traditional Open Versus Minimally Invasive Techniques.
Recently, minimally invasive spine arthrodesis has gained popularity among spine surgeons. Minimally invasive techniques have advantages and disadvantages compared with traditional open techniques. Comparisons between short-term outcomes of minimally invasive transforaminal interbody fusion and open transforaminal interbody fusion in terms of estimated blood loss, postoperative pain, and hospital length of stay have been well documented and generally favor the minimally invasive technique. However, the advantages of minimally invasive transforaminal interbody fusion must be evaluated in the context of long-term results, such as patient-reported outcomes and the success of arthrodesis. Because the literature is equivocal in identifying the superior technique for successful long-term outcomes, more study is needed. Patient safety, the risk of complications, and the cost of these techniques also must be considered.


Mast cell-dependent allergic responses are inhibited by ethanolic extract of adlay (Coix lachryma-jobi L. var. ma-yuen Stapf) testa.
Allergy is an immune dysfunction caused by degranulation from mast cells in the early phase and cytokine secretion in the late phase of the cell. The purpose of this study was to investigate the effects of adlay (Job's tears, Coix lachryma-jobi L. var. ma-yuen Stapf) testa against beta-hexosaminidase release as a marker of degranulation in rat basophilic leukemia (RBL)-2H3 cells. The ethyl acetate fraction from ethanolic extracts of adlay testa (ATE-EtOAc) exhibited potent inhibitory activity that suppressed degranulation from RBL-2H3 cells stimulated by 1 microM A23187. The 20%-80% EtOAc/Hex subfractions of ATE-EtOAc significantly inhibited histamine release with a IC(50) of 75-100 microg/mL. In addition, the ATE-EtOAc subfractions suppressed interleukin (IL)-4, IL-6, and tumor necrosis factor-alpha secretion in RBL-2H3 cells, indicating that adlay testa were able to inhibit cytokine secretion. In order to explore the inhibitory mechanism of adlay testa in mast cell degranulation, we examined the activation of intracellular signaling molecules. Adlay testa inhibited the phosphorylation ERK expression. Furthermore, the two major active compounds, 4-hydroxyacetophenone and p-coumaric acid, were isolated from the ATE-EtOAc subfractions. These results suggest that ATE had an inhibitory effect on allergic response via the ERK signaling transduction in RBL-2H3 cells.


Remotely-pumped network-embedded self-tuning transmitter for 80-Gb/s conventional hybrid TDM/WDM PON with 256-split.
We present a colorless network-embedded self-tuning transmitter assisted by a remotely pumped erbium-doped double-pass amplifier located at the remote node for a conventional hybrid stacked-WDM/TDM-PON. The scheme provides up to 256-split PON with 80-Gb/s aggregate upstream capacity obtained with RSOA direct modulation at 2.5 Gb/s.


A survey of occupational health in the Royal Norvegian Navy.
The aim of this article is to describe possible risk factors in the work environment that can affect the health of staff of the Royal Norwegian Navy (RNoN). The article presents the main results from a subproject related to a major surveillance of the health and work environment in this population. The project was performed as a response to general concerns regarding harmful work environment and negative health effects for these employees. In 2002, a questionnaire was sent out to all the employees in RNoN, and they answered during a period of three months. The overall response rate was 58% (n=2265), 2001 men and 250 women (14 unknown sex). 1581 military employees and 580 civilians participated (104 unknown). Mean age was 38 (range 18-70). Questions about years at work, exposure to chemical, physical and ergonomic hazards were developed for this particular study. Questions about allergy, asthma, hand eczema, hearing loss, cardiovascular disease, diabetes mellitus and cancer were asked. Musculoskeletal disorders were obtained by a standardized instrument. Exposure to noise, heavy lifting, twisted work positions and work close to antennas and communication equipment occurred often in this population. The most commonly reported diseases that might be work related were hand eczema, hearing loss and low back pain. The results indicate the presence of several possible risk factors to health related to the work environment in this population. The project gives a basis for further action regarding the Health Safety and Environment work within RNoN.


Double-check probing of DNA bending and unwinding by XPA-RPA: an architectural function in DNA repair.
The multiprotein factor composed of XPA and replication protein A (RPA) is an essential subunit of the mammalian nucleotide excision repair system. Although XPA-RPA has been implicated in damage recognition, its activity in the DNA repair pathway remains controversial. By replacing DNA adducts with mispaired bases or non-hybridizing analogues, we found that the weak preference of XPA and RPA for damaged substrates is entirely mediated by indirect readout of DNA helix conformations. Further screening with artificially distorted substrates revealed that XPA binds most efficiently to rigidly bent duplexes but not to single-stranded DNA. Conversely, RPA recognizes single-stranded sites but not backbone bending. Thus, the association of XPA with RPA generates a double-check sensor that detects, simultaneously, backbone and base pair distortion of DNA. The affinity of XPA for sharply bent duplexes, characteristic of architectural proteins, is not compatible with a direct function during recognition of nucleotide lesions. Instead, XPA in conjunction with RPA may constitute a regulatory factor that monitors DNA bending and unwinding to verify the damage-specific localization of repair complexes or control their correct three-dimensional assembly.


Informing Investment to Reduce Inequalities: A Modelling Approach.
Reducing health inequalities is an important policy objective but there is limited quantitative information about the impact of specific interventions. To provide estimates of the impact of a range of interventions on health and health inequalities. Literature reviews were conducted to identify the best evidence linking interventions to mortality and hospital admissions. We examined interventions across the determinants of health: a 'living wage'; changes to benefits, taxation and employment; active travel; tobacco taxation; smoking cessation, alcohol brief interventions, and weight management services. A model was developed to estimate mortality and years of life lost (YLL) in intervention and comparison populations over a 20-year time period following interventions delivered only in the first year. We estimated changes in inequalities using the relative index of inequality (RII). Introduction of a 'living wage' generated the largest beneficial health impact, with modest reductions in health inequalities. Benefits increases had modest positive impacts on health and health inequalities. Income tax increases had negative impacts on population health but reduced inequalities, while council tax increases worsened both health and health inequalities. Active travel increases had minimally positive effects on population health but widened health inequalities. Increases in employment reduced inequalities only when targeted to the most deprived groups. Tobacco taxation had modestly positive impacts on health but little impact on health inequalities. Alcohol brief interventions had modestly positive impacts on health and health inequalities only when strongly socially targeted, while smoking cessation and weight-reduction programmes had minimal impacts on health and health inequalities even when socially targeted. Interventions have markedly different effects on mortality, hospitalisations and inequalities. The most effective (and likely cost-effective) interventions for reducing inequalities were regulatory and tax options. Interventions focused on individual agency were much less likely to impact on inequalities, even when targeted at the most deprived communities.


Rationale and methods of the European Food Consumption Validation (EFCOVAL) Project.
The overall objective of the European Food Consumption Validation (EFCOVAL) Project was to further develop and validate a trans-European food consumption method to be used for the evaluation of the intake of foods, nutrients and potentially hazardous chemicals within the European population. The EFCOVAL Project was carried out by 13 institutes from 11 European countries. The main activities were centered on the three main objectives of the project organized in different sub-projects. In EFCOVAL, EPIC-Soft (the software developed to conduct 24-h dietary recalls (24-HDRs) in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study) was reprogrammed and adapted according to prioritized specifications, resulting in a software program working under the Windows operating system. In parallel of the EPIC-Soft development, the repeated 24-HDR method using EPIC-Soft and a food propensity questionnaire was evaluated against biomarkers in 24-h urine collections and in blood samples among adults from Belgium, the Czech Republic, (the South of) France, the Netherlands and Norway. As a result from an expert workshop on a proposed dietary assessment method for children (4-12 years), the suggested method was tested in a feasibility study in Denmark and Spain among children of 4-5, 7-8 and 12-13 years. To ensure that collected data had sufficient detail in food description for the assessment of additives and contaminants to foods the EPIC-Soft databases were adapted. Finally, the EFCOVAL Consortium developed a statistical tool (Multiple Source Method) for estimating the usual intake and distribution, which has been tested using real food consumption data and compared with three other statistical methods through a simulation study. In addition, a methodology was developed to quantify uncertainty due to portion-size estimation in usual intake distributions. The findings of EFCOVAL provide sufficient evidence to conclude that the repeated 24-HDR using EPIC-Soft for standardization in combination with a food propensity questionnaire and modeling of usual intake is a suitable method for pan-European surveillance of nutritional adequacy and food safety among healthy adults and maybe in children aged 7 years and older.


Experimental investigation of the 2D ion beam profile generated by an ESI octopole-QMS system.
In this paper, we have employed an ion imaging approach to investigate the behavior of ions exiting from a quadrupole mass spectrometer (QMS) system that employs a radio frequency octopole ion guide before the QMS. An in-vacuum active pixel detector (Timepix) is employed at the exit of the QMS to image the ion patterns. The detector assembly simultaneously records the ion impact position and number of ions per pixel in every measurement frame. The transmission characteristics of the ion beam exiting the QMS are studied using this imaging detector under different operating conditions. Experimental results confirm that the ion spatial distribution exiting the QMS is heavily influenced by ion injection conditions. Furthermore, ion images from Timepix measurements of protein standards demonstrate the capability to enhance the quality of the mass spectral information and provide a detailed insight in the spatial distribution of different charge states (and hence different m/z) ions exiting the QMS.